U.S. patent application number 13/501494 was filed with the patent office on 2012-08-09 for carrier composition.
Invention is credited to Jeremy James Cottrell, Mahmoud El-Tamimy, Giacinto Gaetano, Paul David Gavin, Nicholas John Kennedy.
Application Number | 20120202780 13/501494 |
Document ID | / |
Family ID | 44194821 |
Filed Date | 2012-08-09 |
United States Patent
Application |
20120202780 |
Kind Code |
A1 |
Gavin; Paul David ; et
al. |
August 9, 2012 |
CARRIER COMPOSITION
Abstract
A carrier composition of the present invention comprises a
phosphate compound of an electron transfer agent and a relatively
high concentration of a polar protic solvent. A biologically active
compound may be formulated with a carrier composition of the
present invention to provide a formulation.
Inventors: |
Gavin; Paul David;
(Chadstone, AU) ; El-Tamimy; Mahmoud; (Meadow
Heights, AU) ; Cottrell; Jeremy James; (Caulfield
South, AU) ; Gaetano; Giacinto; (South Melbourne,
AU) ; Kennedy; Nicholas John; (Boronia, AU) |
Family ID: |
44194821 |
Appl. No.: |
13/501494 |
Filed: |
December 22, 2010 |
PCT Filed: |
December 22, 2010 |
PCT NO: |
PCT/AU2010/001719 |
371 Date: |
April 12, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61289507 |
Dec 23, 2009 |
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Current U.S.
Class: |
514/180 ;
514/179; 514/413; 514/567; 514/626; 514/772; 514/785; 514/788 |
Current CPC
Class: |
A61P 23/00 20180101;
A61K 31/167 20130101; A61K 47/10 20130101; A61K 47/24 20130101;
A61K 31/196 20130101; A61K 31/407 20130101; A61P 29/00 20180101;
A61P 35/00 20180101; A61K 47/16 20130101; A61K 31/4422 20130101;
A61P 9/00 20180101; A61K 31/485 20130101; A61K 9/0014 20130101;
A61K 31/573 20130101; A61K 47/22 20130101; A61P 5/00 20180101 |
Class at
Publication: |
514/180 ;
514/785; 514/788; 514/772; 514/626; 514/567; 514/413; 514/179 |
International
Class: |
A61K 47/24 20060101
A61K047/24; A61K 31/196 20060101 A61K031/196; A61P 5/00 20060101
A61P005/00; A61K 31/573 20060101 A61K031/573; A61P 23/00 20060101
A61P023/00; A61P 29/00 20060101 A61P029/00; A61K 31/167 20060101
A61K031/167; A61K 31/407 20060101 A61K031/407 |
Claims
1. A carrier composition for delivery of a biologically active
compound comprising a phosphate compound of an electron transfer
agent and a polar protic solvent selected from the group consisting
of acyclic alcohols, alkyl esters, ketones and nitriles, wherein
the polar protic solvent concentration is within the range of about
60% w/w to about 90% w/w of the total concentration of the carrier
composition.
2. The carrier composition of claim 1, wherein the polar protic
solvent concentration is within the range of about 65% w/w to about
85% w/w, about 70% w/w to about 80% w/w, or about 50% w/w to about
60% w/w, or about 60% w/w to about 70% w/w, or about 80% w/w to
about 90% w/w.
3. The carrier composition of claim 1, wherein the polar protic
solvent is an acyclic alcohol.
4. The carrier composition of claim 1, wherein the acyclic alcohol
is selected from the group consisting of C.sub.1-C.sub.4 acyclic
alcohols, polyols of C.sub.1-C.sub.4 acyclic alcohols, polymers of
C.sub.1-C.sub.4 acyclic alcohols, and ester, alkyl ester and ether
derivatives thereof.
5. The carrier composition of claim 4, wherein the acyclic alcohol
is ethanol, n-propanol, isopropanol, ethylene glycol, propylene
glycol, polyethylene glycol, diethylene glycol monoethylether or
ethyl acetate.
6. The carrier composition of claim 1, wherein the polar protic
solvent is a ketone.
7. The carrier composition of claim 6, wherein the ketone is methyl
isobutyl ketone or acetone.
8. The carrier composition of claim 1, wherein the polar protic
solvent is a nitrile.
9. The carrier composition of claim 8, wherein the nitrile is
acetonitrile.
10. The carrier composition of claim 1, wherein the electron
transfer agent is a hydroxy chroman.
11. The carrier composition of claim 10, wherein the hydroxy
chroman is a tocopherol or a tocotrienol.
12. The carrier composition of claim 11, wherein the phosphate
compound of tocopherol is selected from the group consisting of
mono-(tocopheryl) phosphate, mono-(tocopheryl) phosphate monosodium
salt, mono-(tocopheryl) phosphate monopotassium salt,
mono-(tocopheryl) phosphate disodium salt, mono-(tocopheryl)
phosphate dipotassium salt, di-(tocopheryl) phosphate,
di-(tocopheryl) phosphate monosodium salt, di-(tocopheryl)
phosphate monopotassium salt, or a mixture thereof.
13. The carrier composition of claim 12, wherein the phosphate
compound of tocopherol is a mixture of a mono-(tocopheryl)
phosphate to a di-(tocopheryl) phosphate.
14. The carrier composition of claim 13, wherein the mixture of a
mono-(tocopheryl) phosphate to a di-(tocopheryl) phosphate is in a
ratio of at least 2:1, or within the range of about 4:1 to about
1:4, or within the range of about 6:4 to about 8:2.
15. The carrier composition of claim 1, wherein the phosphate
compound of an electron transfer agent is present in an amount
within the range of about 0.01% w/w to about 20% w/w, or about
0.01% w/w to about 10% w/w, or about 0.01% w/w to about 5% w/w, or
about 0.01% w/w to about 2% w/w, or about 5% w/w to about 10% w/w,
or about 10% w/w to about 15% w/w, or about 0.05% w/w, or about
0.1% w/w or about 1% w/w of the total concentration of the carrier
composition.
16. Use of a phosphate compound of an electron transfer agent and a
polar protic solvent selected from the group consisting of acyclic
alcohols, alkyl esters, ketones and nitriles in the manufacture of
the carrier composition, wherein the polar protic solvent
concentration is within the range of about 60% w/w to about 90% w/w
of the total concentration of the carrier composition.
17. A process for the preparation of a carrier composition of claim
1 comprising the step of combining the phosphate compound of the
electron transfer agent and the polar protic solvent until complete
homogenisation is achieved.
18. A formulation comprising a carrier composition of claim 1 and a
biologically active compound.
19. The formulation of claim 18, wherein the biologically active
compound is lipophilic having a logP value within the range of
about 1 to about 5.
20. The formulation of claim 18, wherein the biologically active
compound has a relatively low molecular mass and/or a relatively
low melting point.
21. The formulation of claim 18, wherein the biologically active
compound is present in an amount of up to about 30% w/w of the
total concentration of the carrier composition.
22. The formulation of claim 21, wherein the biologically active
compound is selected from the group consisting of lidocaine,
diclofenac, ketorolac, prilocaine, halobetasol, hydrocortisor, and
combinations thereof.
23. The formulation of claim 22, wherein the biologically active
compound is present in an amount of up to 5% w/w of the total
concentration of the carrier composition.
24. A process for the preparation of a formulation of claim 18
comprising the step of adding a biologically active compound to a
carrier composition of claim 1.
25. Use of a carrier composition of claim 1 to improve the delivery
of a biologically active compound formulated with the carrier
composition, or to alter A.D.M.E. properties of a biologically
active compound, or to improve the bioavailability of a
biologically active compound in a subject.
26. A method for treating a subject for a pathological condition
which comprises administering an effective amount of a biologically
active compound that will treat the pathological condition to a
subject in need thereof, wherein the biologically active compound
is formulated in a carrier composition of claim 1.
Description
TECHNICAL FIELD
[0001] The present invention relates to carrier compositions for
delivery of biologically active compounds.
BACKGROUND
[0002] In this specification where a document, act or item of
knowledge is referred to or discussed, this reference or discussion
is not an admission that the document, act or item of knowledge or
any combination thereof was at the priority date, publicly
available, known to the public, part of common general knowledge;
or known to be relevant to an attempt to solve any problem with
which this specification is concerned.
[0003] Drug delivery is the method or process of administering a
pharmaceutical compound to achieve a therapeutic effect in humans
and animals.
[0004] Drug delivery technologies have been developed to improve
bioavailability, safety, duration, onset or release, of the
pharmaceutical compound.
[0005] When developing drug delivery technologies, problems likely
to be encountered include compatibility of the drug delivery system
and the pharmaceutical compound, maintaining an adequate and
effective duration, potential for side effects, and meeting patient
convenience and compliance. As a consequence, many drug delivery
technologies fall short of desired improvements and
requirements.
[0006] Accordingly, there is still a need for alternate drug
delivery systems which effectively deliver drugs.
SUMMARY
[0007] It has surprisingly been found that a carrier composition
comprising a phosphate compound of an electron transfer agent and a
relatively high concentration of a polar protic solvent can improve
the delivery of a biological active compound.
[0008] According to a first aspect of the invention there is
provided a carrier composition for delivery of a biologically
active compound comprising a phosphate compound of an electron
transfer agent and a polar protic solvent, wherein the polar protic
solvent concentration is greater than 50% w/w of the total
concentration of the carrier composition.
[0009] There is also provided use of a phosphate compound of an
electron transfer agent and a polar protic solvent in the
manufacture of the carrier composition.
[0010] There is further provided a process for the preparation of
the carrier composition which comprises the step of combining a
phosphate compound of an electron transfer agent and a polar protic
solvent until complete homogenisation is achieved.
[0011] The polar protic solvent concentration is within the range
of preferably about 60% w/w to about 90% w/w, more preferably about
65% w/w to about 85% w/w, most preferably about 70% w/w to about
80% w/w. In some circumstances, a suitable range may be about 50%
w/w to about 60% w/w, about 60% w/w to about 70% w/w or about 80%
w/w to about 90% w/w.
[0012] In one embodiment the polar protic solvent is an acyclic
alcohol. A C.sub.2-C.sub.3 acyclic alcohol is preferred, and
ethanol and propanol are most preferred.
[0013] The electron transfer agent may be an antioxidant or a
derivatised compound thereof. In a preferred embodiment the
electron transfer agent is a hydroxy chroman, preferably a tocol
such as tocopherol or tocotrienol.
[0014] Phosphate compounds of tocopherol may be selected from the
group consisting of mono-(tocopheryl) phosphate, mono-(tocopheryl)
phosphate monosodium salt, mono-(tocopheryl) phosphate
monopotassium salt, mono-(tocopheryl) phosphate disodium salt,
mono-(tocopheryl) phosphate dipotassium salt, di-(tocopheryl)
phosphate, di-(tocopheryl) phosphate monosodium salt,
di-(tocopheryl) phosphate monopotassium salt, or a mixture
thereof.
[0015] When the carrier composition comprises a mixture of a
mono-(tocopheryl) phosphate to a di-(tocopheryl) phosphate, the
ratio is preferably at least 2:1, more preferably within the range
of about 4:1 to about 1:4, most preferably within the range of
about 6:4 to about 8:2. In preferred embodiments the ratio is about
6:4 or about 8:2.
[0016] The carrier composition comprises a phosphate compound of an
electron transfer agent in an amount within the range of preferably
about 0.01% w/w to about 20% w/w, more preferably about 0.01% w/w
to about 10% w/w, most preferably about 0.01% w/w to about 5% w/w
or about 0.01% w/w to about 1% w/w of the total concentration of
the carrier composition. In one embodiment the carrier composition
comprises a phosphate compound of an electron transfer agent in an
amount within the range of about 0.01% w/w to about 2% w/w,
preferably about 0.05% w/w, about 0.1% w/w or about 1% w/w. In a
further embodiment, a range of about 5% w/w to about 10% w/w or
about 10% w/w to about 15% w/w may be used.
[0017] In a second aspect of the invention there is provided a
formulation comprising the carrier composition and a biologically
active compound.
[0018] There is also provided a process for the preparation of the
formulation which comprises the step of adding a biologically
active compound to the carrier composition.
[0019] In one embodiment, the biologically active compound is
lipophilic having a logP value within the range of about 1 to about
5. The biologically active compound also preferably has a
relatively low molecular mass and a relatively low melting
point.
[0020] A biologically active compound may be present in an amount
of up to about 30% w/w of the total concentration of the carrier
composition.
[0021] In a third aspect of the invention there is provided use of
the carrier composition to improve the delivery of a biologically
active compound formulated with the carrier composition.
[0022] There is also provided use of the carrier composition to
alter A.D.M.E. properties of a biologically active compound.
[0023] There is further provided use of the carrier composition to
improve the bioavailability of a biologically active compound in a
subject.
[0024] In a fourth aspect of the invention there is provided a
method for treating a subject for a pathological condition which
comprises administering an effective amount of a biologically
active compound in the carrier composition. The pathological
conditions include those that can be treated by the biologically
active compound formulated with the carrier composition.
DETAILED DESCRIPTION
[0025] A carrier composition of the present invention comprises a
phosphate compound of an electron transfer agent and a relatively
high concentration of a polar protic solvent. A biologically active
compound may be formulated with a carrier composition of the
present invention to provide a formulation.
[0026] In this specification, except where the context requires
otherwise, the words "comprise", "comprises", and "comprising" mean
"include", "includes", and "including" respectively, i.e. when the
invention is described or defined as comprising specified features,
various embodiments of the same invention may also include
additional features.
Phosphate Compound of an Electron Transfer Agent
[0027] The term "electron transfer agent" refers to a compound that
may be phosphorylated and which, in the non-phosphorylated form,
can accept an electron to generate a relatively stable molecular
radical or can accept two electrons to allow the compound to
participate in a reversible redox system. Examples of electron
transfer agents include antioxidants and derivatives thereof.
[0028] The term "antioxidant" refers to a molecule capable of
slowing or preventing the oxidation of other molecules. Oxidation
is a chemical reaction that transfers electrons from a substance to
an oxidizing agent. Oxidation reactions can produce free radicals,
which start chain reactions that damage cells. Antioxidants
terminate these chain reactions by removing free radical
intermediates, and inhibit other oxidation reactions by being
oxidized themselves. As a result, antioxidants are often reducing
agents.
[0029] Antioxidants are generally classified into two broad
divisions, depending on whether they are soluble in water
(hydrophilic) or in lipids (hydrophobic). Ascorbic acid (vitamin C)
is an example of a water soluble antioxidant. Carotenes, tocopherol
(Vitamin E), retinol (Vitamin A), ubiquinol (the reduced form of
coenzyme Q) and calciferol (Vitamin D) are examples of lipid
soluble antioxidants.
[0030] Carotenes are carotenoids containing no oxygen. Carotenoids
are based on carotenes with one or more hydrogen atoms substituted
by a hydroxyl group and/or some pairs of hydrogen atoms are
substituted by oxygen atoms. The term "hydroxy carotenoids" refers
to carotenes substituted with one or more hydroxyl groups.
Cryptoxanthin is an example of a hydroxy carotenoid: it is closely
related to beta-carotene with only the addition of a hydroxyl
group.
[0031] Vitamin E exists in eight different forms, namely four
tocopherols and four tocotrienols. All feature a chroman ring, with
a hydroxyl group that can donate a hydrogen atom to reduce free
radicals and a hydrophobic side chain which allows for penetration
into biological membranes. Such derivatives of Vitamin E may be
classified as "hydroxy chromans". Both tocopherols and tocotrienols
occur in alpha, beta, gamma and delta forms, determined by the
number and location of methyl groups on the chroman ring. The
tocotrienols differ from the analogous tocopherols by the presence
of three double bonds in the hydrophobic side chain. The various
forms of Vitamin E are shown by Formula (I):
TABLE-US-00001 (I) ##STR00001## R.sub.1 R.sub.2 R.sub.3
.alpha.-tocopherol CH.sub.3 CH.sub.3 CH.sub.3 .alpha.-tocotrienol
CH.sub.3 CH.sub.3 CH.sub.3 .beta.-tocopherol CH.sub.3 H CH.sub.3
.beta.-tocotrienol CH.sub.3 H CH.sub.3 .gamma.-tocopherol H
CH.sub.3 CH.sub.3 .gamma.-tocotrienol H CH.sub.3 CH.sub.3
.delta.-tocopherol H H CH.sub.3 .delta.-tocotrienol H H
CH.sub.3
[0032] Retinol belongs to the family of chemical compounds known as
retinoids. There are three generations of retinoids. First
generation retinoids include retinol, retinal, tretinoin (retinoic
acid, Retin-A), isotretinoin and alitretinoin. Second generation
retinoids include etretinate and its metabolite acitretin. Third
generation retinoids include tazarotene, bexarotene and
adapalene.
[0033] Ubiquinol is a benzoquinol and is the reduced form of
ubiquinone (coenzyme Q.sub.10).
[0034] Calciferol (Vitamin D) comes in several forms. The two major
forms are vitamin D.sub.2 (e.g. ergocalciferol) and vitamin D.sub.3
(e.g. calcitriol, cholecalciferol). The other forms include vitamin
D.sub.1 (molecular compound of ergocalciferol with lumisterol,
1:1), vitamin D.sub.4 (22-dihydroergocalciferol) and vitamin D5
(sitocalciferol, made from 7-dehydrositosterol).
[0035] Any antioxidant or derivative thereof described herein would
be suitable for the present invention. Preferred antioxidants and
derivatives thereof are selected from the group consisting of
carotenoids, hydroxy chromans, carotenoids, retinoids, benzoquinols
and calcitriols. Hydroxy chromans are preferred. Tocols such as a
tocopherol, in any form, is most preferred.
[0036] The term "phosphate compound" refers to a phosphorylated
compound, where a covalent bond is formed between an oxygen atom
(typically originating from a hydroxyl group) of the compound and
the phosphorous atom of a phosphate group (PO.sub.4): in this
context, the compound is an electron transfer agent.
[0037] The phosphate compound may be a phosphate mono-ester,
phosphate di-ester, phosphate tri-ester, pyrophosphate mono-ester,
pyrophosphate di-ester, or a salt or derivative thereof, or a
mixture thereof. The di- and tri-esters may comprise the same
electron transfer agent or different electron transfer agents.
[0038] The "salts" include metal salts such as alkali or alkaline
earth metal salts, for example sodium, magnesium, potassium and
calcium salts. Sodium and potassium salts are preferred.
[0039] The "derivatives" include phosphate compounds where one or
more phosphate protons are replaced by a substituent. Some
non-limiting examples of derivatives include phosphatidyl
derivatives where a phosphate proton is substituted with an
amino-alkyl group, sugar derivatives where a phosphate proton is
substituted with a sugar such as glucose.
[0040] The term "amino-alkyl group" refers to a group comprising an
amino (--NH.sub.2) group and an alkyl group. The term "alkyl"
refers to straight chain, branched chain or cyclic hydrocarbon
groups having from 1 to 8 carbon atoms. Examples include methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl, cyclohexyl, heptyl, and octyl. Phosphatidyl choline
derivatives are most preferred.
[0041] When the electron transfer agent is tocopherol, for example,
the phosphate compounds of tocopherol may be selected from the
group consisting of mono-(tocopheryl) phosphate, mono-(tocopheryl)
phosphate monosodium salt, mono-(tocopheryl) phosphate
monopotassium salt, mono-(tocopheryl) phosphate disodium salt,
mono-(tocopheryl) phosphate dipotassium salt, di-(tocopheryl)
phosphate, di-(tocopheryl) phosphate monosodium salt,
di-(tocopheryl) phosphate monopotassium salt, or a mixture thereof.
These phosphate compounds may be derived from the alpha, beta,
gamma or delta form of tocopherol, or a combination thereof.
[0042] When the carrier composition contains a mixture of a
mono-phosphate ester and a di-phosphate ester, for example a
mono-(tocopheryl) phosphate and di-(tocopheryl) phosphate, the
ratio is preferably at least 2:1, more preferably within the range
of about 4:1 to about 1:4, most preferably within the range of
about 6:4 to about 8:2. The ratio may be about 6:4 or about
8:2.
[0043] The carrier composition comprises a phosphate compound of an
electron transfer agent in an amount within the range of preferably
about 0.01% w/w to about 20% w/w, more preferably about 0.01% w/w
to about 10% w/w, most preferably about 0.01% w/w to about 5% w/w
or about 0.01% w/w to about 1% w/w of the total concentration of
the carrier composition. The carrier composition may comprise a
phosphate compound of an electron transfer agent in an amount
within the range of about 0.01% w/w to about 2% w/w, preferably
about 0.05% w/w, about 0.1% w/w or about 1% w/w. In a further
embodiment, a range of about 5% w/w to about 10% w/w or about 10%
w/w to about 15% w/w may be suitable.
Polar Protic Solvent
[0044] Organic solvents may be grouped as non-polar or polar
aprotic solvents, and polar protic solvents.
[0045] The organic solvent of the present invention is a polar
protic solvent. A "protic solvent" is a solvent that has a hydrogen
atom bound to an oxygen atom or a nitrogen atom as in a hydroxyl
group or an amine group, respectively. More generally, any
molecular solvent which contains a hydrogen ion capable of
dissociation may be considered a protic solvent. Conversely, an
"aprotic solvent" cannot donate hydrogen ions.
[0046] The polar protic solvent may be an acyclic alcohol, alkyl
ester, ketone or nitrile. The acyclic alcohol may be selected from
the group consisting of C.sub.1-C.sub.4 acyclic alcohols including
polyols, polymers and derivatives (e.g. esters, alkyl esters,
ethers) thereof. Some examples of these include ethanol,
n-propanol, isopropanol, glycols such as propylene glycol,
polyethylene glycol (e.g. PEG400), diethylene glycol monoethylether
and ethyl acetate. The ketone may be selected from the group
consisting of methyl isobutyl ketone and acetone. The nitrile may
be acetonitrile.
[0047] The carrier composition may comprise only one polar protic
solvent; however, a combination of polar protic solvents may also
be used. For the avoidance of any doubt, it is to be noted that the
singular forms "a", "an" and "the" as used herein for any feature
should be read as encompassing plural forms, unless the context
clearly indicates otherwise.
[0048] The carrier composition has a relatively high polar protic
solvent concentration. The polar protic solvent concentration is
within the range of preferably about 60% w/w to about 90% w/w, more
preferably about 65% w/w to about 85% w/w, most preferably about
70% w/w to about 80% w/w. The polar protic solvent concentration
may be about 70% w/w or about 80% w/w. In some circumstances a
suitable range of polar protic solvent concentration may be about
50% w/w to about 60% w/w, about 60% w/w to about 70% w/w or about
80% w/w to about 90% w/w.
Biologically Active Compound
[0049] The term "biologically active compound" refers to any
chemical substance that has a biological effect in humans or
animals for medical, therapeutic, cosmetic and veterinary purposes,
and encompasses pharmaceuticals including drugs, cosmeceuticals,
nutraceuticals, and nutritional agents. It will be appreciated that
some of biologically active compounds can be classified in more
than one of these classes.
[0050] A wide range of biologically active compounds may be
delivered with a carrier composition of the present invention.
Preferably, the biologically active compound is lipophilic, and has
a relatively low molecular mass and a relatively low melting
point.
[0051] The term "lipophilicity" refers to the ability of a chemical
compound to dissolve in fats, oils, lipids, and non-polar solvents
such as hexane or toluene. The lipophilicity of a biologically
active compound may be assessed by its octanol/water partitioning
coefficient (logP value), which is believed to approximate membrane
permeability.
[0052] Transdermally permeable biologically active compounds are
likely to have a logP value between about 2.5 to about 3.5. It has
been found that biologically active compounds having a logP value
within this range and biologically active compounds having a logP
value outside this range (either above or below) formulated with a
carrier composition of the present invention are more transdermally
permeable, that is, biologically active compounds having a logP
value within the range of about 1 to about 5. Therefore, the
biologically active compound may have a logP value within the range
of about 1 to about 2.5, within the range of about 2.5 and about
3.5, and within the range of about 3.5 to about 5.
[0053] Not wishing to be bound by theory, it is believed that a
carrier composition of the present invention can alter one or more
A.D.M.E. (Absorption, Distribution, Metabolism, and Excretion)
properties of a biological active compound to improve the delivery
of the biological active compound. To be an effective biological
active compound, the biological active compound not only must be
active against a target, but also possess the appropriate A.D.M.E.
properties necessary to make it suitable for use as a biological
active compound.
[0054] A "relatively low molecular mass" refers to a molecular mass
of less than about 1000 Daltons, preferably less than about 500
Daltons, more preferably within the range of about 200 Daltons to
about 300 Daltons.
[0055] A "relatively low melting point" refers to a melting point
of less than about 400.degree. C.
[0056] A wide range of biologically active compounds may be
delivered with the carrier composition of the present invention.
Examples include, but are not limited to, cardiovascular drugs, in
particular antihypertensive agents (e.g. calcium channel blockers
(or calcium antagonists)) and antiarrhythmic agents; congestive
heart-failure pharmaceuticals; inotropic agents; vasodilators; ACE
inhibitors; diuretics; carbonic anhydrase inhibitors; cardiac
glycosides; phosphodiesterase inhibitors; a blockers; .beta.
blockers; sodium channel blockers; potassium channel blockers;
.beta.-adrenergic agonists; platelet inhibitors; angiotensin II
antagonists; anticoagulants; thrombolytic agents; treatments for
bleeding; treatments for anaemia; thrombin inhibitors;
antiparasitic agents; antibacterial agents; antiinflammatory
agents, in particular non-steroidal antiinflammatory agents
(NSAIDs), more particularly COX-2 inhibitors; steroidal
antiinflammatory agents; prophylactic antiinflammatory agents;
antiglaucoma agents; mast cell stabilisers; mydriatics; agents
affecting the respiratory system; allergic rhinitis
pharmaceuticals; alpha-adrenergic agonists; corticosteroids;
chronic obstructive pulmonary disease pharmaceuticals;
xanthine-oxidase inhibitors; antiarthritis agents; gout treatments;
autacoids and autacoid antagonists; antimycobacterial agents;
antifungal agents; antiprotozoal agents; anthelmintic agents;
antiviral agents especially for respiratory , herpes,
cyto-megalovirus, human immunodeficiency virus and hepatitis
infections; treatments for leukemia and kaposi's sarcoma; pain
management agents in particular anaesthetics and analgesics,
opioids including opioid receptor agonists, opioid receptor partial
agonists, opioid antagonist or opioid receptor mixed
agonist-antagonists; neuroleptics; sympathomimetic pharmaceuticals;
adrenergic agonists; drugs affecting neurotransmitter uptake or
release; anticholinergic pharmaceuticals; antihaemorrhoid
treatments; agents to prevent or treat radiation or
chemotherapeutic effects; liopgenisis drugs; fat reducing
treatments; antiobesity agents such as lipase inhibitors;
sympathomimetic agents; treatments for gastric ulcers and
inflammation such as proton pump inhibitors; prostaglandins; VEGF
inhibitors; antihyperlipidemic agents, in particular statins; drugs
that affect the central nervous system (CNS) such as antipsychotic,
antiepileptic and antiseizure drugs (anticonvulsants), psychoactive
drugs, stimulants, antianxiety and hypnotic drugs, antidepressant
drugs; antiparkinson's pharmaceuticals; hormones and fragments
thereof such as sex hormones; growth hormone antagonists;
gonadotropin releasing hormones and analogues thereof; steroid
hormones and their antagonists; selective estrogen modulators;
growth factors; antidiabetic pharmaceuticals such as hypoglycaemic
agents; H1, H2, H3 and H4 antihistamines; agents used to treat
migraine headaches; asthma pharmaceuticals; cholinergic
antagonists; glucocorticoids; androgens; antiandrogens; inhibitors
of adrenocorticoid biosynthesis; osteoporosis treatments such as
biphosphonates; antithyroid pharmaceuticals; suncreens, sun
protectants and filters; cytokine agonists; cytokine antagonists;
anticancer drugs; antialzheimer drugs; HMGCoA reductase inhibitors;
fibrates; cholesterol absorption inhibitors; HDL cholesterol
elevating agents; triglyceride reducing agents; antiageing or
antiwrinkle agents; antibacterial agents; antiacne agents;
antioxidants; hair treatments and skin whitening agents; small
molecule therapeutic agents for the treatment, or prevention of
human and animal diseases such as allergy/asthma, arthritis,
cancer, diabetes, growth impairment, cardiovascular diseases,
inflammation, immunological disorders, baldness, pain,
ophthalmological diseases, epilepsy, gynaecological disorders, CNS
diseases, viral infections, bacterial infections, parasitic
infections, GI diseases, obesity, and haemological diseases.
[0057] A person skilled in the art of the invention would be able
to determine whether or not a particular biologically active
compound would be suitable for use with the carrier composition of
the present invention. Some specific non-limiting examples of
suitable biologically active compounds include:
Anaesthetics:
[0058] including amino-ester and amino-amide anaesthetics such as
benzocaine, chloroprocaine, cocaine, reserpine, guanethidine,
cyclomethycaine, dimethocaine/larocaine, propoxycaine,
procaine/novocaine, proparacaine, tetracaine/amethocaine;
articaine, bupivacaine, carticaine, cinchocaine/dibucaine,
etidocaine, levobupivacaine, lidocaine/lignocaine, mepivacaine,
piperocaine, prilocaine, ropivacaine, trimecaine, propofol,
halothane, enflurane barbiturates, benzodiazepines, neostigmine and
ketamine
Alkylating Agents:
[0059] including carmustine, cyclophosphamide, ifosfamide,
streptozotocin and mechlorethamine
Calcium Channel Blockers:
[0060] including amlodipine, aranidipine, azelnidipine,
barnidipine, benidipine, cilnidipine, clevidipine, cronidipine,
darodipine, dexniguldipine, efonidipine, elnadipine, elgodipine,
felodipine, flordipine, furnidipine, iganidipine, isradipine,
lacidipine, lemildipine, lercanidipine, manidipine, mesuldipine,
nicardipine, nifedipine, niludipine, nilvadipine, nimodipine,
nisoldipine, nitrendipine, olradipine, oxodipine, palonidipine,
pranidipine, sagandipine, sornidipine, teludipine, tiamdipine,
trombodipine, watanidipine, verapamil, gallopamil, benzothiazepine,
diltiazem, mibefradil, bepridil, fluspirilene and fendiline
Antiarrhythmic and Antiangina Agents:
[0061] including amiodarone, disopyramide, flecainide acetate,
quinidine sulphate, nitroglycerine, ranolazine, amiodarone,
isosorbide and alteplase
Antibacterial, Antibiotic and Antiacne Agents:
[0062] including amoxicillin, ampicillin, azithromycin, benethamine
penicillin, bleomycin, benzoyl peroxide, cinoxacin,
chloramphenicol, daunorubicin, plicamycin, fluoroquinolones,
ciprofloxacin, clarithromycin, clindamycin, clindesse, clofazimine,
chlorohexidine gluconate, cloxacillin, demeclocycline, doxycycline,
erythromycin, ethionamide, imipenem, indomethacin, lymocycline,
minocycline, nalidixic acid, nitrofurantoin, penicillin,
rifampicin, spiramycin, sodium sulfacetamide, sulphabenzamide,
sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine,
sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline,
cephalexin, cefdinir, triclosan, ofloxacin, vancocin, glyburide,
mupirocin, cefprozil, cefuroxime axetil, norfloxacin, isoniazid,
lupulone, D-penicillamine, levofloxacin, gatifoxacin, and
trimethoprim
Anticancer:
[0063] including doxorubicin, 6-thioguanine, paclitaxel, docetaxel,
camptothecin, megestrol acetate, navelbine, cytarabine,
fludarabine, 6-mercaptopurine, 5-fluorouracil, teniposide,
vinblastine, vincristine, cisplatin, colchicine, carboplatin,
procarbazine and etopside
Antidepressants, Antipsychotics and Antianxiety:
[0064] including alprazolam, amoxapine, bentazepam, bromazepam,
clorazipine, clobazam, clotiazepam, diazepam, lorazepam,
flunitrazepam, flurazepam, lormetazepam, medazepam, nitrazepam,
oxazepam, temazepam, maprotiline, mianserin, nortriptyline,
risperidone, sertraline, trazodone, baloperidol, trimipramine
maleate fluoxetine, ondansetron, midazolam, chlorpromazine,
haloperidol, triazolam, clozapine, fluopromazine, fluphenazine
decanoate, fluanisone, perphenazine, pimozide, prochlorperazine,
sulpiride, thioridazine, paroxitine, citalopram, bupropion,
phenelzine, olanzapine, divalproex sodium and venlafaxine
Opioids:
[0065] including opioid receptor agonists and antagonists,
compounds which exhibit mixed agonist/antagonist activity and
compounds which exhibit partial agonist activity, including
morphine, depomorphine, etorphine, diacetylmorphine, hydromorphone,
oxymorphone, levorphanol, methadone, levomethadyl, meperidine,
fentanyl, sufentanyl, alfentanil, codeine, hydrocodone, oxycodone,
thebaine, desomorphine, nicomorphine, dipropanoylmorphine,
benzylmorphine, ethylmorphine, pethidine, methadone, tramadol,
dextropropoxyphene; naloxone and naltrexone; buprenorphine,
nalbuphine, butorphanol, pentazocine and ethylketocyclazocine
Tricyclics:
[0066] including azothiopine, amitriptyline, famotidine,
promethazine, paroxatine, oxcarbazapine and mertazapine
Antidiabetics:
[0067] including acetohexamide, chlorpropamide, glibenclaraide,
gliclazide, glipizide, metformin, tolazamide, glyburide,
glimepiride and tolbutamide
Antiepileptics:
[0068] including beclamide, carbamazepine, gapapentin, tiagabine,
vigabatrin, topiramate, clonazepam, ethotoin, methoin,
methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione,
phenacemide, phenobarbitone, phenyloin, phensuximide, primidone,
sulthiamine, phenytoin sodium, nirofurantoin monohydrate,
gabapentin, lamotrigine, zonisamide, ethosuximide and valproic
acid
Hypnotics/Sedatives and Muscle Relaxants:
[0069] including zolpidem tartrate, amylobarbitone, barbitone,
butobarbitone, pentobarbitone, brotizolam, carbromal,
chlordiazepoxide, chlormethiazole, ethinamate, meprobamate,
methaqualome, cyclobenzaprene, cyclobenzaprine, tizanidine,
baclofen, butalbital, zopiclone, atracurium, tubocurarine and
phenobarbital
Antifungal, Antiprotazoal and Antiparasitic Agents:
[0070] including amphotericin, butoconazole nitrate, clotrimazole,
econazole nitrate, fluconazole, flucytosine, griseofulvin,
itraconazole, ketoconazole, miconazole, natamycin, nystatin,
sulconazole nitrate, terconazole, tioconazole and undecenoic acid;
benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline,
diloxanide furoate, dinitolmide, furzolidone, metronidazole,
nimorazole, nitrofurazone, ornidazole, terbinafine, clotrimazole,
chloroquine, mefloquine, itraconazole, Pyrimethamine, praziquantel,
quinacrine, mebendazole and tinidazole
Antihypertensive and Cardiac Therapeutic Agents:
[0071] including candesartan, hydralazine, clonidine, triamterene,
felodipine, gemfibrozil, fenofibrate, nifedical, prazosin,
mecamylamine, doxazosin, dobutamine and cilexetil
Antimigraine Agents:
[0072] including dihydroergotamine mesylate, ergotamine tartrate,
methysergide maleate, pizotifen maleate and sumatriptan
succinate
Antimuscarinic Agents:
[0073] including atropine, benzhexol, biperiden, ethopropazine,
hyoscyamine, mepenzolate bromide, oxybutynin, oxyphencylcimine and
tropicamide
Antineoplastic Agents (Or Immunosuppressants):
[0074] including aminoglutethimide, amsacrine, azathioprine,
busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine,
etoposide, lomustine, melphalan, mercaptopurine, methotrexate,
mitomycin, mitotane, mitozantrone, procarbazine, tamoxifen citrate,
testolactone, tacrolimus, mercaptopurine and sirolimus
Antiparkinsonian Agents:
[0075] including bromocriptine mesylate, levodopa, tolcapone,
ropinirole, bromocriptine, hypoglycaemic agents such as
sulfonylureas, biguanides, a-glucosidase inhibitors,
thaiazolidinediones, cabergoline, carbidopa and lysuride
maleate
Antithyroid Agents:
[0076] including carbimazole and propylthiouracil
Antiviral Drugs:
[0077] including amantadine, retinovir, cidofovir, acyclovir,
famciclovir, ribavirin, amprenavir, indinavirm, rimantadine and
efavirenz, penciclovir, ganciclovir, vidarabine, abacavir,
adefovir, apmrenavir, delavirdine, didanosine, stavudine,
zalcitabine, zidovudine, enfuvirtide and interferon
Cardiac Inotropic Agents:
[0078] including amrinone, milrinone, digitoxin, digoxin,
enoximone, lanatoside C and medigoxin
Hypo and Hyper Lipidemic Agents:
[0079] including fenofibrate, clofibrate, probucol, ezetimibe and
torcetrapib
Antiinflammatory:
[0080] including meoxicam, triamcinolone, cromolyn, nedocromil,
hydroxychloroquine, montelukast, zileuton, zafirlukast and
meloxicam
Antihistamine:
[0081] including fexofenadine, chloral hydrate, hydroxyzine,
promethazine, cetirazine, cimetidine, clyclizine, meclizine,
dimenhydrinate, loratadine, nizatadine and promethazine
Antiulcer:
[0082] including omeprazole, lansoprazole, pantoprazole and
ranitidine
Diuretics:
[0083] including hydrochlorothiazide, amiloride, acetazolamide,
furosemide and torsemide
NSAIDs:
[0084] including arylalkanoic acid sub-group of class which
includes diclofenac, aceclofenac, acemetacin, alclofenac,
bromfenac, etodolac, indometacin, indometacin farnesil, nabumetone,
oxametacin, proglumetacin, sulindac and tolmetin; 2-arylpropionic
acid (profens) sub-group of class which includes alminoprofen,
benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen,
fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam,
indoprofen, ketoprofen, ketorolac, loxoprofen, miroprofen,
naproxen, oxaprozin, pirprofen, suprofen, tarenflurbil and
tiaprofenic acid; and N-arylanthranilic acid (fenamic acid)
sub-group of class which includes flufenamic acid, meclofenamic
acid, mefenamic acid and tolfenamic acid; tromethamine, celecoxib,
nepafenac, aspirin, rofecoxib, naproxen, sulindac, piroxicam,
pheylbutazone, tolmetin, indomethacin, acetominophen (paracetamol),
tramadol and propoxyphene
Retinoids:
[0085] including first generation retinoids such as retinol,
retinal, tretinoin (retinoic acid, Retin-A), isotretinoin and
alitretinoin; second generation retinoids such as etretinate and
its metabolite acitretin; third generation retinoids such as
tazarotene, bexarotene and adapalene
Hormones and Steroids:
[0086] including adrenocorticotrophic hormone (ACTH), antidiruetic
hormone (vasopressin), atrial-nartreuretic factor (ANF),
beclomethasone, cortisone, scopolamine, dopamine, epinephrine,
catecholamines, cholecystokinin, clomiphene citrate, danazol,
dexamethasone, diethylstilbestrol (DES), ethinyl estradiol,
fludrocortison, finasteride, follicle stimulating hormone, gastrin,
hydroxyprogesterone, leptin, luteinizing hormone,
medroxyprogesterone acetate, mestranol, quinestrol,
methyltestosterone, nandrolone, norethindrone, norethisterone,
norgestrel, estradiol, conjugated oestrogens, oxandrolone,
oxytocin, prednisone, progesterone, prolactin, protogalndins,
somatostatin, stanozolol, stibestrol, thyroxine, prednisolone
phosphate, triamcinolone, mifepristone acetonide, budesonide,
levothyroxine, testosterone, testosterone cypionate,
fluoxymesterone, flutamide, mometasone furoate, cyproterone,
fluromethalone, goserelin, leuprolide, calcitonin, halobetasol,
hydrocortisol and tibolone
Statins and Derivatives:
[0087] including atorvastatin, fluvastatin, lovastatin, nystatin,
rosuvastatin, pravastatin, orlistat and simvastatin
Stimulants:
[0088] including amphetamine, phentermine, tyramine, ephedrine,
metaraminol, phenylephrine, dexamphetamine, dexfenfluramine,
fenfluramine, nicotine, caffeine and mazindol
Vasocontrictors:
[0089] including desmopressin
Vasodilitors:
[0090] including carvedilol, terazosin, phentolamine and
menthol
Antialzheimers:
[0091] including levetiracetam, levitiracetam and donepezil
ACE Inhibitors:
[0092] including benzapril, enalapril, ramipril, fosinopril sodium,
lisinopril, minoxidil, isosorbide, rampril and quinapril
Beta Adrenoreceptor Antogonists:
[0093] including atenolol, timolol, pindolol, propanolol
hydrochloride, bisoprolol, esmolol, metoprolol succinate,
metoprolol and metoprolol tartrate
Angiotensin II Antagonists: including losartan
Platelet Inhibitors:
[0094] including abciximab, clopidrogel, tirofiban and aspirin
Alcohols and Phenols:
[0095] including tramadol, tramadol hydrochloride, allopurinol,
calcitriol, cilostazol, soltalol, urasodiol bromperidol,
droperidol, flupenthixol decanoate, albuterol, albuterol sulphate,
carisoprodol, chlobetasol, ropinirol, labetalol, and
methocarbamol
Ketones and Esters:
[0096] including amioderone, fluticasone, spironolactone,
prednisone, triazodone, desoximetasone, methyl prednisdone,
benzonatate nabumetone and buspirone
Antiemetics:
[0097] including metoclopramide
Ocular Treatments:
[0098] including dorzolamide, brimonidine, olopatadine,
cyclopentolate, pilocarpine and echothiophate
Anticoagulant and Antithrombitic Agents:
[0099] including warfarin, enoxaparin and lepirudin
Treatments for Gout:
[0100] including probenecid and sulfinpyrazone
COPD and Asthma Treatments:
[0101] including ipratropium
Treatments for Osteoporosis:
[0102] including raloxifene, pamidronate and risedronate.
[0103] Particularly preferred biologically active compounds include
lidocaine, diclofenac, ketoralac, prilocaine, halobetasol,
hydrocortisol and combinations thereof.
[0104] It is to be understood that pharmaceutically acceptable
derivatives of biologically active compounds are included within
the scope of the present invention.
[0105] The term "pharmaceutically acceptable derivatives" includes,
but is not limited to, pharmaceutically acceptable salts, esters,
salts of such esters, ethers, or any other derivative including
prodrugs and metabolites, which upon administration to a subject in
need is capable of providing, directly or indirectly, a
biologically active compound as otherwise described herein.
[0106] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et al. describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66:1-19, 1977. Examples of pharmaceutically acceptable
nontoxic acid addition salts are salts of an amino group formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid, or malonic acid or by using other
methods used in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.
[0107] The term "pharmaceutically acceptable ester" refers to
esters which are hydrolysed in vivo and include those that break
down readily in the human body to leave the parent compound or a
salt thereof. Suitable ester groups include, for example, those
derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters include formates, acetates, propionates,
butyrates, acrylates and ethylsuccinates.
[0108] The term "pharmaceutically acceptable prodrugs" as used
herein refers to those prodrugs of the biologically active
compounds which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of a subject with
undue toxicity, irritation, allergic response, and the like,
commensurate with a reasonable benefit/risk ratio, and effective
for their intended use, as well as the zwitterionic forms, where
possible, of the compounds of the invention. The term "prodrug"
refers to compounds that are rapidly transformed in vivo to yield
the parent compound of the above formula, for example by hydrolysis
in blood. A thorough discussion is provided in T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and
Pergamon Press, 1987.
[0109] A biologically active compound may be present in an amount
of up to about 30% w/w of the total concentration of the carrier
composition. The amount of biologically active compound is
preferably up to about 10% w/w, more preferably up to about 6% w/w,
most preferably within the range of about 0.1% w/w to about 5%
w/w.
[0110] The carrier composition improves the delivery of a
biological active compound by altering the A.D.M.E. properties of
the biological active compound. Not wishing to be bound by theory,
it is believed that the A.D.M.E. properties of a biological active
compound are altered because the combination of a phosphate
compound of an electron transfer agent and a relatively high
concentration of a polar protic solvent changes the solubility of
the biologically active compound in different barriers (skin,
mucous membranes, muscle, and so on). This solubility change
affects the residence time of the drug in these tissues and delays,
or shortens, the time at which the drug will be introduced to the
elimination phase. Accordingly, a carrier composition of the
present invention can provide the advantage of: [0111] reduced side
effects (i.e. minimalising the unrequired systemic effect); [0112]
restricting the biologically active compound distribution to
specific areas (e.g. drug-targeting); [0113] improving patient
compliance (e.g. less amount used, smaller application); [0114]
improving aesthetic feeling (e.g. fast-drying); and [0115]
increasing duration of action and/or shorten onset.
[0116] A carrier composition of the present invention may also
improve the bioavailability of a biologically active compound in a
subject.
[0117] The present invention can also be used in a method for
treating a subject for a pathological condition which comprises
administering an effective amount of a biologically active compound
in a carrier composition of the present invention. The pathological
conditions include those that can be treated by the biologically
active compound formulated with the carrier composition.
[0118] The term "subject" as used herein refers to any animal
having symptoms associated with or caused by a pathological
condition, which requires treatment with a biologically active
compound. The animal may be a mammal, preferably a human, or may be
a non-human primate or non-primates such as used in animal model
testing. While it is particularly contemplated that a formulation
of the invention is suitable for use in medical treatment of
humans, it is also applicable to veterinary treatment, including
treatment of companion animals such as dogs and cats, and domestic
animals such as horses, ponies, donkeys, mules, llama, alpaca,
pigs, cattle and sheep, or zoo animals such as primates, felids,
canids, bovids, and ungulates.
[0119] Generally, the terms "treating", "treatment" and the like
are used herein to mean affecting a subject, tissue or cell to
obtain a desired pharmacological and/or physiological effect. The
effect may be prophylactic in terms of completely or partially
preventing one or more pathological conditions, and/or may be
therapeutic in terms of a partial or complete cure of one or more
pathological conditions.
Routes of Administration
[0120] Routes of administration can broadly be divided into a three
categories by effect, namely, "topical" where the desired effect is
local, so the substance is applied directly where its action is
desired, "enteral" where the desired effect is systemic (non-local)
so the substance is given via the digestive tract, and "parenteral"
where the desired effect is systemic, so the substance is given by
routes other than the digestive tract.
[0121] The U.S. Food and Drug Administration recognise 111 distinct
routes of administration. The following is a non-limiting list of
examples of routes of administration.
[0122] Examples of topical routes of administration having a local
effect include epicutaneous (onto the skin) and intravitreal (onto
the eye).
[0123] Examples of enteral routes of administration having a
systemic (non-local) effect include any form of administration that
involves any part of the gastrointestinal tract, such as oral (into
the mouth), intranasal (into the nose), rectal (into the rectum),
and vaginal (into the vagina).
[0124] Examples of parenteral routes of administration by
injection, infusion or diffusion having a systemic effect include
intravenous (into a vein), intraarterial (into an artery),
intramuscular (into a muscle), intracardiac (into the heart),
subcutaneous (under the skin), percutaneous (via needle-puncture
into the skin), intradermal (into the skin itself), intrathecal
(into the spinal canal), intraperitoneal (infusion or injection
into the peritoneum), intravesical infusion (infusion into the
urinary bladder), epidural (injection or infusion into the epidural
space), transdermal or transcutaneous (diffusion through the intact
skin), transmucosal (diffusion through a mucous membrane),
insufflation (diffusion through the nose), inhalational (diffusion
through the mouth), sublingual (under the tongue), and buccal
(absorbed through cheek near gumline).
[0125] Formulations according to the present invention can be in
any suitable administration form (see, for example, Pharmaceutics
and Pharmacy Practice, J. B. Lippincott Company, Philadelphia, Pa.,
Banker and Chalmers, eds., pages 238-250 (1982)). Examples of
suitable administration forms includes, but are not limited to,
solutions, liquids, suspensions, gels, poultices, reservoir
patches, and creams. The formulations may also be prepared and
stored in one form and delivered in another, for example the
formulation may be stored in liquid form and delivered in the form
of a foam. The formulations and can be prepared by any methods well
known in the art of pharmacy such as described in Remington J. P.,
The Science and Practice of Pharmacy, ed. A. R. Gennaro, 20.sup.th
edition, Lippincott, Williams and Wilkins Baltimore, Md. (2000).
Such methods include the step of bringing into association the
biologically active compound with the carrier, and then, if
necessary, shaping the formulation into the desired product.
Preparation of a Carrier Composition
[0126] A carrier composition of the present invention may be
prepared by a variety of techniques.
[0127] One method of preparing the carrier composition involves
combining the components of the carrier composition, in suitable
quantities, with stirring, until complete homogenisation is
achieved.
[0128] In a preferred method, a phosphate compound of an electron
transfer agent is combined with a polar protic solvent, and warmed
at 40.degree. C. until a solution is formed. An aqueous phase,
usually of lower volume, is heated to 40.degree. C. and then added
drop wise to the solution to form the carrier composition.
Alternately in some circumstances the phosphate compound of the
electron transfer agent combined with the polar protic solvent may
be added dropwise to the aqueous phase. The final pH of the carrier
composition may be adjusted to improve stability, for example by
the addition of sodium hydroxide. The carrier composition is
usually a clear to translucent solution.
[0129] Depending on the solubility and stability of the
biologically active compound, it may be dissolved in either the
aqueous or solvent phase.
[0130] The carrier composition may optionally further comprise one
or more excipients. A person skilled in the art of the invention
would appreciate suitable excipients which could be included with a
carrier composition or a formulation of the present invention. The
choice of other excipients will depend on the characteristics of
the biologically active compound and the form of administration
used. Examples of other excipients include additional solvents such
as water, thickeners or gelling agents, surfactants, buffers,
emollients, sweeteners, disintegrators, flavours, colours,
fragrances, electrolytes, appearance modifiers, film foaming
polymers, propellants and the like. Suitable sweeteners include
sucrose, lactose, glucose, aspartame or saccharin. Suitable
disintegrators include corn starch, methylcellulose,
polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
Suitable gelling agents include hydroxy propyl cellulose (HPC) and
carbopol. Suitable flavours include peppermint oil, oil of
wintergreen, cherry, orange or raspberry flavouring. Suitable
propellants include butane, carbon dioxide, ethane,
hydrochloroflurocarbons, isobutane, nitrogen, nitrous oxide,
propane, dimethyl ether, isopentanol, pentane and mixtures thereof
such as Propellant A-46 (20% propane and 80% isobutane). The
relatively high concentration of organic solvent may avoid the need
for a further preservative to be added; however if considered
necessary, suitable preservatives that may be added include sodium
benzoate, methylparaben, propylparaben, and sodium bisulphite.
[0131] The amount of excipient or excipients, if present, is
preferably up to about 10% w/w, more preferably up to about 5% w/w,
most preferably up to about 3% w/w, and even more preferably either
0.01-3% w/w or 0.1-1% w/w of the total concentration of the carrier
composition.
[0132] The carrier composition and formulation according to the
present invention have been found to be physically stable, have no
particle size larger than 300nm. There is also no spontaneous
sol-gel transformation.
FIGURES
[0133] The examples will be described with reference to the
accompanying figures in which:
[0134] FIG. 1 shows the transdermal delivery of formulations
comprising oxycodone in Franz cells in vitro;
[0135] FIGS. 2A and 2B show the relative behaviour of formulations
comprising oxycodone in a dose response;
[0136] FIG. 3 shows comparative skin deposition results of
formulations comprising lidocaine;
[0137] FIG. 4 shows comparative skin deposition results of
formulations comprising diclofenac; and
[0138] FIG. 5 shows comparative skin deposition results of
formulations comprising ketorolac.
EXAMPLES
[0139] Various embodiments/aspects of the present invention will
now be described with reference to the following non-limiting
examples.
Example 1
[0140] Carrier compositions were prepared according to the
preferred method described above.
[0141] Each of the five carrier compositions comprised 1% w/w of a
mixture of mono-(tocopheryl) phosphate and di-(tocopheryl)
phosphate in a ratio of 8:2 and water, and the following polar
protic solvent concentrations:
TABLE-US-00002 % polar protic solvent (i) 50% w/v ethanol (ii) 60%
w/v ethanol (iii) 70% w/v ethanol (iv) 80% w/v ethanol (v) 90% w/v
ethanol
Method for Thermal Cycling
[0142] The carrier compositions were refrigerated at about
5.degree. C. for approximately 12 hours, and then subjected to a
temperature of about 30.degree. C. for approximately 12 hours for 3
cycles. Between each change of temperature the carrier compositions
were left at room temperature for 3 hours and observed for any
turbidity and precipitation.
TABLE-US-00003 Clarity of solution Precipitate (i) slightly turbid
none (ii) clear none (iii) clear none (iv) clear none (v) clear
none
Example 2
[0143] This example compares percutaneous oxycodone delivery in
vitro using a formulation of the present invention (Formulation 2A)
and a formulation which comprises a low polar protic solvent
concentration (Formulation 2B). Details of the each formulation are
as follows:
TABLE-US-00004 Formulation 2A Components Amounts A mixture of
mono-(tocopheryl) phosphate and 1% w/w di-(tocopheryl) phosphate in
a ratio of 6:4 Isopropanol 70% w/w Oxycodone 5% w/w Molecular mass:
315.40 g/mol Melting point: 218-220.degree. C. Hydroxypropyl
cellulose (HPC) H 1% w/w QS dH.sub.2O
TABLE-US-00005 Formulation 2B Components Amounts A mixture of
mono-(tocopheryl) phosphate and 2% w/w di-(tocopheryl) phosphate in
a ratio of 7:3 Isopropanol 10% w/w Ethanol 10% w/w Oxycodone 1.5%
w/w Carbopol NF10 0.25% w/w.sup. QS dH.sub.2O
[0144] Formulation 2A had a pH of 6. Formulation 2B had a pH of
6.4.
Method
[0145] Formulation 2A was prepared according to the preferred
method described above. Formulation 2B was similarly prepared.
[0146] Full thickness rat abdominal skin was used in 12m1 vertical
Franz diffusion cells (PermeGear, Pa.). Rats were killed by
asphyxiation using CO.sub.2 gas and the abdominal area carefully
shaved and excised. All underlying fat and connective tissue was
removed. Skin was frozen flat between sheets of aluminium foil and
stored at -20.degree. C. until the morning of experimentation.
[0147] PBS was used in the Franz cells as the receptor solution (12
ml) and the Franz cells had a surface area of 1.77 cm.sup.2. During
experiments, the cells were maintained at 32.degree. C. Finite
dosing (40 .mu.l) was used to approximate the conditions to be used
in vivo. Receiver solutions were sampled regularly over 4 hours to
determine the percutaneous oxycodone absorption and analysed using
HPLC. The results are presented in FIG. 1. The results are the
averages of n=8-10 diffusion cells conducted across two separate
days. Bars represent SEM.
Results
[0148] It was found that Formulation 2A, which has a polar protic
solvent concentration of 70% w/w, could maintain a concentration of
oxycodone of 5% w/w. Formulation 2B, which has a polar protic
solvent concentration of 20% w/w on the other hand, could only
maintain a maximum concentration of oxycodone of 1.5% w/w.
[0149] Although both formulations were able to transdermally
deliver oxycodone, the results show that, after 4 hours,
approximately 130 .mu.g of oxycodone was delivered by Formulation
2A compared to approximately 18 .mu.g delivered by Formulation
2B.
[0150] The drying time for Formulation 2A led to a rapid rate of
delivery (i.e. flux), in addition to the increased total amount.
The linear flux (J) of percutaneous oxycodone absorption for
Formulation 2A was 40 .mu.g.h/cm.sup.2, whereas Formulation 2B had
flux of 5.54 .mu.g.h/cm.sup.2.
[0151] While both the increased flux and amount of oxycodone
delivered may be partially attributed to the increased oxycodone
concentration (and subsequent dose), the results show that
Formulation 2A also had higher bioavailability. The percentage of
oxycodone delivered from the total applied dose was approximately
8% with Formulation 2A compared to only approximately 3% with
Formulation 2B.
Conclusion
[0152] The formulation of the present invention (Formulation 2A)
was capable of an increased oxycodone concentration relative to
Formulation 2B. Formulation 2A also showed better percutaneous
oxycodone absorption, both with respect to the rate and total
oxycodone delivered, and superior bioavailability.
Example 3
[0153] This example is a dose response study that compares the
performance of a formulation of the present invention (Formulation
3A) and an aqueous formulation (Formulation 3B) to determine their
relative behaviour in a dose response. Details of the each
formulation are as follows:
TABLE-US-00006 Formulation 3A Components Amounts A mixture of
mono-(tocopheryl) phosphate and 1% w/w di-(tocopheryl) phosphate in
a ratio of 6:4 Isopropanol 70% w/w Oxycodone 5% w/w Molecular mass:
315.40 g/mol Melting point: 218-220.degree. C. HPC H 1% w/w QS
dH.sub.2O
TABLE-US-00007 Formulation 3B Components Amounts A mixture of
mono-(tocopheryl) phosphate 10.8% w/w monosodium salt and
di-(tocopheryl) phosphate in a ratio of 2:1 Oxycodone.cndot.HCl
0.7% w/w Molecular mass: 351.83 g/mol Pemulen 0.7% w/w QS
dH.sub.2O
[0154] Formulation 3A had a pH of 6. Formulation 3B had a pH of
8.
Method
[0155] Formulation 3A was prepared according to the preferred
method described above. Formulation 3B was similarly prepared.
[0156] Full thickness rat abdominal skin was used in 12m1 vertical
Franz diffusion cells (PermeGear, Pa.). Rats were killed by
asphyxiation using CO.sub.2 gas and the abdominal area carefully
shaved and excised. All underlying fat and connective tissue was
removed. Skin was frozen flat between sheets of aluminium foil and
stored at -20.degree. C. until the morning of experimentation.
[0157] PBS was used in the Franz cells as the receptor solution (12
ml) and the Franz cells had a surface area of 1.77 cm.sup.2. During
experiments, the cells were maintained at 32.degree. C. Finite
dosing (20-60 .mu.l) was used to approximate the conditions to be
used in vivo. Receiver solutions were sampled regularly over 4
hours to determine the percutaneous oxycodone absorption and
analysed using HPLC. The results are presented in FIGS. 2A and
2B.
Results
[0158] Formulation 3A had increased transdermal flux compared to
Formulation 3B. The use of a high polar protic solvent
concentration (Formulation 3A) allowed equivalent amounts of the
preferred form of oxycodone (base; 5% w/w) to be formulated.
[0159] With equivalent doses between 10-20 .mu.l/cm.sup.2,
Formulation 3A delivered twice as much oxycodone as Formulation 3B,
with both formulations exhibiting a good dose response. At a dose
of 30 .mu.l/cm.sup.2, no further increase in transdermal delivery
is seen with Formulation 3B. The dose response continues for
Formulation 3A even at the highest dose of 30 .mu.l/cm.sup.2.
Conclusion
[0160] This dose response study particularly shows that a
formulation of the present invention (Formulation 3A) allows for
wider dynamic range in dose responses.
Example 4
[0161] This example compares the stability, skin deposition and
other properties of a formulation of the present invention
(Formulation 4A) and a formulation which comprises a low polar
protic solvent concentration (Formulation 4B). Details of the each
formulation are as follows:
TABLE-US-00008 Formulation 4A Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 8:2 Ethanol 80% w/w Lidocaine base 5% w/w Molecular
mass: 234.34 Melting point: 68.degree. C. Hydroxypropyl
cellulose(GPHX grade, where G is the 3% w/w Molecular mass grade,
PHX means pharmaceutical grade.) QS dH.sub.2O
TABLE-US-00009 Formulation 4B Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 2:1 Ethanol 30% w/w Lidocaine base 1% w/w Molecular
mass: 234.34 Melting point: 68.degree. C. Carbopol (CP934) 1% w/w
QS dH.sub.2O
Method
[0162] Formulation 4A was prepared according to the preferred
method described above. Formulation 4B was similarly prepared.
Results
[0163] The results of a visual stability test showed that, after 3
days of storage, there were no physical changes noted with
Formulation 4A whereas a precipitate had formed with Formulation
4B.
[0164] After 4 hours of administration, Formulation 4A had a
significant skin deposition (.mu.g) compared to Formulation 4B, as
shown in FIG. 3.
Conclusion
[0165] The results showed that a formulation of the present
invention (Formulation 4A) was stable and had improved delivery
compared to Formulation 4B.
Example 5
[0166] This example compares the stability, skin deposition and
other properties of a formulation of the present invention
(Formulation 5A) and a formulation which comprises a low polar
protic solvent concentration (Formulation 5B). Details of the each
formulation are as follows:
TABLE-US-00010 Formulation 5A Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 6:4 Isopropanol 70% w/w Diclofenac diethylamine 2%
w/w Hydroxypropyl cellulose (GPHX grade, where G is the 3% w/w
Molecular mass grade, PHX means pharmaceutical grade.) QS
dH.sub.2O
TABLE-US-00011 Formulation 5B Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 6:4 Isopropanol 10% w/w Diclofenac diethylamine 1%
w/w Hydroxypropyl cellulose (GPHX grade, where G is the 0.6%
w/w.sup. Molecular mass grade, PHX means pharmaceutical grade.) QS
dH.sub.2O
Method
[0167] Diclofenac Formulation 5A was prepared according to the
preferred method described above. Formulation 5B was similarly
prepared.
Results
[0168] The results of a visual stability test showed that, after 3
days of storage, there were no physical changes noted with
Formulation 5A whereas a precipitate had formed with Formulation
5B.
[0169] After 4 hours of administration, Formulation 5A had a
significant skin deposition (.mu.g) compared to Formulation 5B, as
shown in FIG. 4. In FIG. 4, Formulations 5A and 5B are also
compared to the commercially available product comprising
diclofenac Voltaren.RTM..
Conclusion
[0170] The results showed that a formulation of the present
invention (Formulation 5A) was stable and had improved delivery
compared to Formulation 5B.
Example 6
[0171] This example compares the stability, skin permeation and
other properties of a formulation of the present invention
(Formulation 6A) and a formulation which comprises a low polar
protic solvent concentration (Formulation 6B). Details of the each
formulation are as follows:
TABLE-US-00012 Formulation 6A Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 6:4 Isopropanol 70% w/w Ketorolac tromethamine 2% w/w
Hydroxypropyl cellulose (GPHX grade, where G is the 3% w/w
Molecular mass grade, PHX means pharmaceutical grade) QS
dH.sub.2O
TABLE-US-00013 Formulation 6B Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 6:4 Isopropanol 10% w/w Ketorolac tromethamine 2% w/w
Hydroxypropyl cellulose (GPHX grade, where G is the 0.6% w/w.sup.
Molecular mass grade, PHX means pharmaceutical grade) QS
dH.sub.2O
Method
[0172] Formulation 6A was prepared according to the preferred
method described above. Formulation 6B was similarly prepared.
[0173] A skin permeation test similar to that conducted for Example
2 was also conducted with the formulations.
Results
[0174] The results of a visual stability test showed that, after 3
days of storage, there were no physical changes noted with
Formulation 6A whereas a precipitate had formed with Formulation
6B.
[0175] After 4 hours of administration, Formulation 6A had a
significant skin deposition (.mu.g) compared to Formulation 6B, as
shown in FIG. 5.
Conclusion
[0176] The results showed that a formulation of the present
invention (Formulation 6A) was stable and had improved delivery
compared to Formulation 6B.
Example 7
[0177] This example compares the stability and other properties of
a formulation of the present invention (Formulation 7A) and a
formulation which comprises a low polar protic solvent
concentration (Formulation 7B). Details of the each formulation are
as follows:
TABLE-US-00014 Formulation 7A Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 6:4 Isopropanol 70% w/w Felodipine 1% w/w QS
dH.sub.2O
TABLE-US-00015 Formulation 7B Components Amounts A mixture of
mono-(tocopheryl) phosphate and di- 1% w/w (tocopheryl) phosphate
in a ratio of 2:1 Isopropanol 10% w/w Felodipine 1% w/w
Hydroxypropyl cellulose (GPHX grade, where G is the 3% w/w
Molecular mass grade, PHX means pharmaceutical grade.) QS
dH.sub.2O
Method
[0178] Formulation 7A was prepared according to the preferred
method described above. Formulation 7B was similarly prepared.
Results
[0179] The results of a visual stability test showed that, after 3
days of storage, there were no physical changes noted with
Formulation 7A whereas a precipitate had formed with Formulation
7B.
[0180] After 4 hours of administration, Formulation 7A had a
significant skin deposition (.mu.g) compared to Formulation 7B.
Conclusion
[0181] The results showed that a formulation of the present
invention (Formulation 7A) was stable and had improved delivery
compared to Formulation 7B.
[0182] It will be understood to persons skilled in the art of the
invention that many modifications may be made without departing
from the spirit and scope of the invention.
* * * * *